Faculty Collaboration Database

Activity of irinotecan and the tyrosine kinase inhibitor CEP-751 in medullary thyroid cancer. J Clin Endocrinol Metab 2006 Jan;91(1):79-84

Date

11/03/2005

Pubmed ID

16263812

DOI

10.1210/jc.2005-1882

Scopus ID

2-s2.0-30344439815 (requires institutional sign-in at Scopus site)   42 Citations

Abstract

CONTEXT: Medullary thyroid cancer (MTC) is a cancer of the parafollicular C cells that commonly presents with an inherited or acquired RET gene mutation. There is currently no effective systemic treatment for MTC.

OBJECTIVE: The objective of this study was to investigate a systemic therapeutic approach to treat MTC. We studied the sensitivity of an MTC cell line and xenograft to irinotecan, alone and in combination with the tyrosine kinase inhibitor, CEP-751.

RESULTS: In TT cell culture and xenografts, irinotecan treatment was highly effective. This effect was augmented by treatment with CEP-751. Treatment of TT cell xenografts resulted in durable complete remission in 100% of the mice, with median time to recurrence of 70 d for irinotecan alone and more than 130 d for irinotecan plus CEP-751. Although irinotecan induced an S phase checkpoint arrest in TT cells, CEP-751 in combination with irinotecan resulted in a loss of this arrest. CEP-751 induced a loss in the induction of the DNA repair program marked by phospho-H2AX and the checkpoint pathway marked by the activated Chk1 pathway.

CONCLUSIONS: Irinotecan treatment was highly effective in a preclinical model of human MTC, resulting in complete remission in 100% of the xenografts treated. The duration of remission was further enhanced by combination with the kinase inhibitor, CEP-751. These results suggest that irinotecan, alone or in combination, may be useful for the treatment of MTC.

Author List

Strock CJ, Park JI, Rosen DM, Ruggeri B, Denmeade SR, Ball DW, Nelkin BD

Author

Jong-In Park PhD Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Blotting, Western
Camptothecin
Carbazoles
Carcinoma, Medullary
Cell Cycle
Cell Division
Cell Line, Tumor
Checkpoint Kinase 1
Enzyme Inhibitors
Histones
Humans
Mice
Mice, Nude
Neoplasm Transplantation
Protein Kinases
Protein-Tyrosine Kinases
S Phase
Signal Transduction
Thyroid Neoplasms
Transplantation, Heterologous
cdc25 Phosphatases